Link Between PCOS & T2D

Epidemiology

The epidemiological evidence linking PCOS with T2D derives mainly from cross-sectional observational studies, retrospective studies and short-term prospective studies. In one study by Gambineri and colleagues, a high prevalence of impaired glucose tolerance (IGT) of 15.7% among women with PCOS was demonstrated.[37] More recently, Moran and colleagues published a meta-analysis on the prevalence of IGT and T2D among women with PCOS that included 35 studies from a selection of >2100 studies.[38] Compared with control women, there was an increased prevalence of IGT (odds ratio [OR]: 2.48; BMI-matched studies: OR: 2.54), and T2D (OR: 4.43; BMI-matched studies: OR: 4.00) among women with PCOS.[38] In addition to T2D, PCOS is also associated with metabolic syndrome. As outlined previously, estimates of prevalence rates of metabolic syndrome in PCOS range between 34 and 46%.[3,4,6]

Given that PCOS and T2D are both obesity-related conditions, and the importance of insulin resistance in the pathogenesis of each, it is perhaps not surprising that there are similarities in epidemiology. However, what is also clear from the published data is that even when BMI is matched for between PCOS and control women, an epidemiological link between PCOS and T2D is still apparent. One implication of these data is that there are likely to be factors independent of obesity (e.g., PCOS-related insulin resistance) that link PCOS and T2D epidemiologically, in addition to obesity-related factors. Although current evidence supports an increased prevalence of IGT and T2D amongst women with PCOS, our current lack of long-term prospective studies in this field obviates the ability to quantify the lifetime risk of developing T2D in women with PCOS, and the risk-factors for the development of T2D associated with PCOS.

Given the epidemiological concurrence of PCOS and T2D, the question arises regarding pathogenic overlap between these two conditions. The pathogenesis of T2D includes a combination of insulin resistance and β-cell dysfunction.[39] Insulin resistance is also a feature of many women with PCOS, particularly those with obesity.[2] As outlined previously, there is some controversy regarding insulin resistance in lean women with PCOS, with some data to support a lack of insulin resistance in this subgroup.[32,33] However, the majority of obese women with PCOS appear to manifest insulin resistance.[2,12] The presence of insulin resistance in PCOS was first reported over 30 years ago,[40] and insulin resistance in PCOS is now well recognized.[2,30] The association of weight loss and use of insulin-sensitizing drugs with improvements in phenotypic features of PCOS support the hypothesis that insulin resistance plays an important role in the development of PCOS.[2] It would therefore seem clear that PCOS and T2D are linked pathogenically by insulin resistance, which in turn is influenced by obesity.

One of the cardinal features of T2D is β-cell dysfunction and consequent insulin deficiency.[39] By contrast, hyperinsulinemia (secondary to insulin resistance) is likely to play a key role in the development of PCOS. Therefore, a key difference between T2D and PCOS would appear to be related to β-cell function. In women with PCOS, insulin stimulates ovarian theca cells, enhancing biosynthesis of ovarian androgens such as testosterone and causing arrest of ovarian follicle development.[41,42] Hyperinsulinemia is also likely to have adverse effects on other tissues including the liver (i.e., suppression of sex hormone-binding globulin production), adrenal and pituitary gland.[2] The steroidogenic effects of insulin in the context of insulin resistance can be explained through impairment of the PI3K-mediated insulin signal transduction pathway, with preservation of signaling through the alternative MAPK pathway (which typically mediates the effects of insulin on cell growth).[43] These postinsulin receptor effects are likely to pertain to both T2D and PCOS.[43,44] Evidence from in vitro studies of such an effect in PCOS comes from the observation of reduced abundance of GLUT4 from adipocytes in women with PCOS (compared with adipocytes from weight-matched control women) despite there being no abnormalities in insulin receptor number or affinity.[45]

Although hyperinsulinemia is likely to be important in the development of PCOS, data from studies on β-cell function in PCOS are conflicting, including reports of reduced β-cell function[46–48] and enhanced β-cell acute insulin secretion during an oral glucose tolerance test.[49–51] It seems likely, therefore, that β-cell function, as with many other aspects of PCOS, is heterogeneous among women with this condition. A suggestion for future research in this field would be to explore the progression of β-cell function over time in women with PCOS. While insulin resistance appears to be an important factor in the development of both PCOS and T2D, β-cell decline and failure with consequent insulin deficiency appears to be confined to T2D and represents an important distinction between T2D and PCOS.

Genetic Links

The epidemiology and etiology of PCOS and T2D are closely linked.[15] It is logical, therefore, to examine the role of T2D-genetic susceptibility variants as candidate genes for the development of PCOS. Variants in two genes, TCF7L2 and KCNJ11, have been demonstrated to display powerful associations with T2D[52–55] and this is likely to be mediated via impairment of insulin secretion.[53,55] The question arises, therefore, whether such T2D genetic variants are also implicated in susceptibility to the development of PCOS. Our own group have published data from an association study based on a large cohort of women from the UK with PCOS (n = 369) versus 2574 UK population controls, and in 540 symptomatic PCOS cases and 1083 controls (recruited from the Northern Finland Birth Cohort of 1966 [NFBC66]).[56] We demonstrated no association of TCF7L2 single nucleotide polymorphisms (SNPs) rs7903146 and rs12255372, which are significantly associated with the risk of T2D, with susceptibility to the development of PCOS or with androgen levels in the UK group, and no association of either TCF7L2 SNP with features of PCOS in the Finnish group. Our data were corroborated by a large study on 58 SNPs mapping to TCF7L2 in >600 PCOS cases and >550 control women, data from which also showed no association of TCF7L2 variants with susceptibility to the development of PCOS.[57] Our group also published data on the E23K polymorphism within KCNJ11, based on a large UK cohort of >370 PCOS cases and >2570 population controls and on 550 women with symptoms of PCOS and >1100 controls from the NFBC66.[58] We also showed no association between the KCNJ11 E23K polymorphism and PCOS, or between this polymorphism and androgen measures.[58] Our data were supported by the findings of a Greek study that also showed no association between KCNJ11 E23K variants and susceptibility to development of PCOS.[59]

Given the importance of impaired insulin secretion in the development of T2D, it is also logical to examine any association between variants in the insulin gene and susceptibility to development of PCOS. The insulin gene variable number of tandem repeats is a series of 14bp or 15bp repeats that regulate insulin gene transcription, and is located within the 5' regulatory element of the insulin gene.[60] Although controversy exists in the literature,[13] we found, in a large multicohort study involving >400 UK PCOS cases, >1000 UK controls and >1500 women from the NFBC66, no evidence for an association of the insulin gene variable number of tandem repeats with susceptibility to development of PCOS.[60]

Data from a GWAS on subjects with T2D showed that variants within the FTO gene are associated with the development of T2D, and that this association is likely to be driven by effects on BMI.[21] Our group showed for the first time, association of a genome-sequence variant (FTO rs9939609) and susceptibility for development of PCOS in 463 women from the UK with PCOS versus >1300 female controls.[23] Following adjustments for differences in BMI, the analyses suggested that the effects of FTO variants on PCOS susceptibility are at least, in part, driven by effects on fat mass, although other effects could not be excluded.[23]

To summarize, the association of obesity with PCOS is genetically corroborated by data on FTO variants from our own group,[23,61] and the association of FTO variants with T2D is well established.[21] However, despite the influence on fat mass that genetically links T2D and PCOS, there is no evidence to implicate other T2D-susceptibility variants, such as TCF7L2 and KCNJ11, in the development of PCOS. Based on both the genetic and clinical characteristics of PCOS and T2D, it would appear, therefore, that the genetic architecture of these two conditions is qualitatively distinct and that impairment of β-cell function, in contrast to T2D, does not appear to be an essential element in the development of PCOS.

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References

Authors and Disclosures

Authors and Disclosures

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Executive Summary

Polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that is associated with a high-risk of development of Type 2 diabetes mellitus (T2D).

PCOS and T2D are both obesity-related conditions that share insulin resistance as an important pathogenic factor.

β -cell Function in PCOS & Diabetes

β-cell dysfunction and hypoinsulinemia are clearly important in the pathogenesis of diabetes. By contrast, women with PCOS often manifest hyperinsulinemia and controversy exists regarding β-cell function, which is likely to be heterogeneous.

Genetic Corroboration Between PCOS, Obesity & T2D

Our best evidence for a genetic link between T2D & PCOS relates to variants within the FTO gene; this genetic link is likely to result from effects of FTO variants on fat mass, with each condition being obesity-related.

The genetic architecture of PCOS and T2D (with regards to variants that influence β-cell function) are qualitatively distinct.

Links Between PCOS & Type 1 Diabetes

The link between PCOS and Type 1 diabetes mellitus results from the effects of supraphysiological concentrations of insulin within the systemic circulation following exogenous subcutaneous dosing of insulin, and the consequent co-gonadotrophic effects of insulin on ovarian and adrenal steroidogenesis.

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